The principal objective of the proposed research is to continue development and characterization of a colon-specific, prodrug- based delivery system. Hydrophilic prodrug derivatives of antiinflammatory drugs will be prepared synthetically. The prodrugs include dexamethasone and prednisolone glycosides and the hemisuccinate of 5-aminosalicylate. These compounds are poorly absorbed in the stomach and small intestine. Once the compounds reach the large intestine and the high concentration of microbial enzymes, the promoiety is designed to be hydrolyzed releasing the free drug, which can then be absorbed by the colonic mucosa. This delivery system should be effective in the localized treatment of inflammatory bowel disease (IBD). This study will evaluate all aspects of the delivery, release, and absorption of antiinflammatory drugs with this delivery system in both normal and disease-simulated (carrageenan-induced colitis) guinea pigs. Also, the ability of this delivery system to treat simulated IBD in the guinea pig will be evaluated. The stability of the prodrugs in solution at several pH levels (2.5, 6.0, and 7.5) and intestinal contents (in vitro) will be evaluated. The prodrugs (and respective parent drugs) will be administered to both normal and diseased animals by gastric intubation. The animals will later be sacrificed, and the location and extent of hydrolysis in the gastrointestinal tract will be determined. Any differences in delivery to the lower bowel between normal and diseased animals will be noted. In a separate set of experiments, the pharmacokinetic characteristics of this delivery system will be evaluated. The bioavailability and mean absorption time of the free drugs from their prodrug forms (and as free drugs) will be measured. The concentration of free drug in colonic tissues following oral administration of the prodrugs will be compared with tissue concentrations of free drug following oral administration of free drug and i.v. administration of the free drug. Guinea pigs will be administered 3% degraded carrageenan in their drinking water to induce ulceration of the cecum and colon. These animals will be used to evaluate any changes in the pharmacokinetics relative to normal animals as well as the ability of this delivery system to treat IBD relative to the traditional route (oral of administration of the free drug).